title: Korean red ginseng extract induces proliferation to differentiation transition of human acute promyelocytic leukemia cells via MYC-SKP2-CDKN1B axis.
abstract: BACKGROUND
  Korean red ginseng has been used as traditional medicine in East Asia. Recent scientific research revealed multiple effects of Korean red ginseng, including anticancer activity. To evaluate the effect of Korean red ginseng extract (KRGE) in acute promyelocytic leukemia (APL) and elucidate its molecular mechanism.
  
  
  METHODS
  NB4 cells were treated with 1mg/ml KRGE for 48 h and examined for cell proliferation and differentiation. Cell cycle distribution of KRGE-treated cells was analyzed and the expression level of G1 phase regulators was determined. MYC was overexpressed by retroviral transduction and its effect on SKP2 and CDKN1B gene expression, cell proliferation, cell cycle and differentiation was evaluated in KRGE-treated cells.
  
  
  RESULTS
  KRGE alone was sufficient to induce granulocytic differentiation accompanied with growth inhibition. KRGE treatment resulted in cell cycle arrest at the G1 phase with augmented Cdkn1b proteins without changes in transcript levels. Cycloheximide treatment revealed reduced degradation of Cdkn1b protein by KRGE. In addition, KRGE treatment reduced expression of MYC and SKP2 genes, both at mRNA and protein levels. Upon ectopic expression of MYC, the effect of KRGE was reversed with lesser reduction and induction of SKP2 gene and Cdkn1b protein, respectively. Taken together, these results suggest a sequential molecular mechanism from MYC reduction, SKP2 reduction, Cdkn1b protein stabilization, G1 phase arrest to granulocytic differentiation by KRGE in human APL.
  
  
  CONCLUSIONS
  KRGE induces leukemic proliferation to differentiation transition in APL through modulation of the MYC-SKP2-CDKN1B axis.
authors.affiliation: Department of Biomedical Science, Graduate School of Biomedical Science and Bioengineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Republic of Korea; Hanyang Biomedical Research Institute, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Republic of Korea. Electronic address: joejo0517@hotmail.com.
authors.forename: Sungsin
authors.initials: S
authors.lastname: Jo
authors.forename: Hongki
authors.initials: H
authors.lastname: Lee
authors.forename: Sojin
authors.initials: S
authors.lastname: Kim
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Heekyoung
authors.initials: H
authors.lastname: Chung
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D005894:Panax; D010936:Plant Extracts / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C436291:CDKN1B protein, human; D010936:Plant Extracts; D016271:Proto-Oncogene Proteins c-myc; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: AML; APL; ATO; ATRA; Acute promyelocytic leukemia (APL); BSA; CDKN1B; CHX; Differentiation; FBS; KRGE; Korean red ginseng extract; Korean red ginseng extract (KRGE); NBT; P/D transition; PBS; PCR; PML-RARA; RT-PCR; SKP2; WST; acute myeloid leukemia; acute promyelocytic leukemia; all-trans retinoic acid; arsenic trioxide; bovine serum albumin; cycloheximide; fetal bovine serum; nitro blue tetrazolium; phosphate-buffered saline; polymerase chain reaction; proliferation/differentiation transition; promyelocytic leukemia-retinoic acid receptor alpha; reverse transcription- polymerase chain reaction; water-soluble tetrazolium salt